The present invention relates to novel 15(R)-5 fluoroprostacyclins of Formula I ##STR2## which, surprisingly, have been found to possess outstanding platelet aggregation inhibition activity without hypotensive effects at platelet aggregation inhibition (i.e., anti-thrombotic) doses.
The natural prostacyclin substance is a physiologically active substance of the formula ##STR3## The shorthand designation of the compound is PGI.sub.2 whereas the chemical name is (5Z)-9-deoxy-6,9.alpha.-epoxy-.DELTA..sup.5 -PGF.sub.1. See, for example, R. A. Johnson et al., J. Am. Chem. Soc. 99, 4182 (1977); R. A. Johnson et al., Prostaglandins, 12, 915 (1976); C. Pace-Asciak and L. S. Wolfe, Biochemistry, 10, 3657 (1971). The natural PGI.sub.2 compound has a number of centers of chirality, including those at C-8, C-9, C-11, C-12 and C-15 carbon atoms. The hydroxy group at C-15 in the natural PGI.sub.2 molecule lies below the plane of the cyclopentane ring with the ring substantially in the plane of the page. In the R,S priority designation system, the C-15 position is designated 15S in the natural PGI.sub.2.
PGI.sub.2 and related cyclic prostaglandins have been demonstrated to elicit a number of biological responses including, but not limited to, inhibition of blood platelet aggregation, lowering of blood pressure, stimulation or relaxation of smooth muscle, inhibition of gastric secretion and protection of gastric mucosa, induction of luteolysis, stimulation of uterine contraction, etc. See, for example, J. R. Vane et al., Prostacyclin, Raven Press, N.Y., 1979.
U.S. Pat. No. 4,178,367 discloses PGI.sub.2 derivatives of the Formula: ##STR4## in which the wavy line attached to the carbon atom in the 15 position represents .alpha. or .beta. configuration (i.e., S or R-configuration) or mixtures thereof. Accordingly, the carbon atom at C-15 may be designated as 15S or 15R. The patentees indicate that the above prostacyclin analogs possess pharmacological properties typical of prostaglandins in a selective fashion, in particular hypotensive activity, inhibitory activity on blood platelet aggregation, relaxing activity of artery, etc. Data are presented indicating that a 15S hydroxy derivative, specifically (5Z,13E)-(9.alpha.,11.alpha.,15S)-6,9-epoxy-11,15-dihydroxy-15-(3 propyl)cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid methyl ester has greater blood pressure lowering activity compared to a 15R derivative, specifically, (5Z,13E)-(9.alpha.,11.alpha.,15R)-6,9 epoxy-11,15-dihydroxy-15-(1-butyl)-cyclobutyl-16,17,18,19,20 pentanorprosta-5,13-dienoic acid methyl ester. The data presented suggest that the 15R derivative is between about 10 and 25 times less active than the 15S compound indicated with respect to blood pressure lowering activity. With respect to blood platelet aggregation inhibition activity, the patentees indicate that the 15S-15-(3-propyl)(cyclopentyl) derivative demonstrates 50% inhibition of ADP-induced blood platelet aggregation at a concentration of 1.35 times 10.sup.-3 ug/ml. whereas the 15R-15-(1-butyl)cyclobutyl derivative produces 50% inhibition at a concentration of 4.2 times 10.sup.-3 .mu.g/ml. From these data it is apparent that the 15S derivative is only very slightly more active than the 15R derivative with respect to in vitro inhibition of platelet aggregation.
There is no in vivo platelet aggregation inhibition data presented in the foregoing U.S. Pat. No. 4,178,367 from which one could draw any conclusions as to any differences in the separation of anti-aggregatory properties vs. hypotensive properties with respect to 15R or 15S derivatives. Further, it is noted that the 15R and 15S compounds discussed above are not otherwise structurally the same (i.e., different alkyl-cycloalkyl substituents are present at the 15 position) and, therefore, any differences in activities may be due to the influence of such different substituents. Moreover, the foregoing patent does not disclose any 5-fluoroprostacyclin derivatives. Inasmuch as the patentees indicate that the C-15 position may have either the R or S configuration or even mixtures thereof, it is evident that no therapeutic advantage is recognized or ascribed to either diastereomer over the other.
In a manner analogous to U.S. Pat. No. 4,178,367, Gandolfi et al., in discussing the structure-activity relationships among certain prostacyclin analogs, suggests that epimerization of the 15-hydroxy group, while compatible with the preservation of a certain anti-aggregatory activity, suppresses, at least in the anesthetized rat, the hypotensive effects. See Gandolfi et al., "Prostacyclin Analogs: Structure-Activity Relationships", Prostaglandins and Cardiovascular Disease, Raven Press, New York, 1981, page 184. The analogs described do not include any 5-fluoro derivatives. However, contrary to the foregoing publication, Flohe et al., in discussing structure-activity relationships of a series of prostacyclin analogs, state that as with natural prostacyclin, the carbon atom at C-15 has to be present in the S-configuration. See Flohe et al., Arzneim-Forsch/Drug Res , 33 (11) No. 9 (1983). In Table 4 of the foregoing publication, the authors compiled data on inhibition of in vitro platelet aggregation for representative pairs of antipodes and conclude that in all cases investigated, the S-isomer is more active than the R-isomer by roughly two orders of magnitude.
Halogenated PGI.sub.2 derivatives have previously been proposed in order to enhance the stability of natural PGI.sub.2. For example, European Patent Application Publication No. 0054795 discloses halogenated .DELTA..sup.5 -prostacyclins, i.e., PGI.sub.2, as well as halogenated .DELTA..sup.6 -prostacyclins which are designated as .DELTA..sup.6 -PGI.sub.1 in this publication to distinguish from natural PGI.sub.2 -type prostacyclins when the double bond is present between the C-5 and C-6 positions. The foregoing publication excludes 5-monofluorinated PGI.sub.2 compounds from within the scope of the disclosed invention. In discussing the various centers of chirality in the prostacyclin molecule, the inventors observe that there are two kinds of stereoisomers with regard to the asymmetric carbon atom at the 15-position in both the disclosed PGI.sub.1 and PGI.sub.2 structures and that the invention encompasses both possible stereoisomers as well as mixtures thereof. Accordingly, with respect to the C-15 carbon atom bearing the hydroxy group, it is evident that no distinction between 15R and 15S derivatives was made between these stereoisomers with respect to biological activity, stability or otherwise. Regarding biological activity presented in the foregoing European publication, 7-fluoro-PGI.sub.2 sodium salt and 5-chloro-PGI.sub.2 sodium salt were tested in comparison to natural PGI.sub.2 with respect to hypotensive activity and both in vitro and extra vivo inhibitory activity of platelet aggregation, as well as activity in the inhibition of metastasis of malignant tumors. From the tests conducted, the inventors conclude that both the 7-fluoro and 5-chloro PGI.sub.2 derivatives (sodium salts) have stronger activities with respect to the inhibition of platelet aggregation in comparison with their blood pressure lowering activities compared to PGI.sub.2 (sodium salt) and therefore have higher selectivity of pharmacological activity than PGI.sub.2. From the results obtained, the ratio of blood pressure lowering activity (effective dose causing a 20% lowering of the mean blood pressure) and the platelet aggregation inhibiting activity (minimum concentration to obtain 50% inhibition of platelet aggregation) was calculated. These data indicate that PGI.sub.2 has an effective ratio of 1 whereas the 7-fluoro derivative has a ratio of 32 and the 5-chloro derivative has a ratio of 4.
U.S. Pat. No. 4,324,730 discloses prostaglandin and prostacyclin compounds wherein a fluorine atom may be substituted in any one or more of the 4,4;7,7;10,10; and 5 positions. The foregoing patent pertains only to .DELTA..sup.5 -prostacyclins, i.e., PGI.sub.2. Although a general reaction scheme is proposed, no specific method for the preparation of a 5-monofluorinated PGI.sub.2 compound is disclosed. Also, the only statement made with respect to stereoisomers is that appended moieties may be either in the .alpha. or .beta. stereochemical configuration in the molecule and no distinction or preference is noted for either stereochemical configuration and, further, no specific biological test data are presented.
European Patent Application (Publication No. 062303, Oct. 13, 1983), assigned to the assignee of this invention, discloses 5-fluoro prostacyclins, including 5,6- or 6,7-unsaturated derivatives thereof along with the process for their preparation. The foregoing published application does not detail the stereochemistry of the 5-position fluoro group or the 15-hydroxy group.
In contrast to the research conducted heretofore, applicants have focused on the potential significance of the specific stereochemistry at the C-15 carbon atom of the prostacyclin structure and have, surprisingly, found that in spite of the absence of any reported distinction or preference in the prior art, that the stereochemistry at the C-15 position is determinative of outstanding in vivo biological properties. More specifically, it has now been found that compounds of Formula I wherein the hydroxy substituted carbon atom at the 15-position is in the R configuration, coupled with the presence of a fluoro group in the C-5 position possess valuable platelet aggregation inhibition properties while at the same time demonstrate virtually no blood pressure lowering effects, thereby providing for the first time a selective therapeutic anti-aggregatory effect in a stabilized cyclic prostaglandin.